Molecule block switches off colon cancer stem cell renewal in mice

A team of geneticists has identified and blocked
the molecule that drives human colorectal cancer stem cell renewal
in mice, as a proof of concept that this method could be used to
prevent relapse.

John Dick of the Princess Margaret Cancer Centre
headed up the study, which was published this week inNature Medicine. He was the first person to identify
the existence of cancer stem cells incertain types of
leukaemia, revealing the hierarchy that exists within
a tumour and paving the way for an entirely new approach to
tackling cancer.

"We've identified that not every colon cancer
cell is equal, some cells have stem cell properties and they lie at
the root of colon cancer," says Dick in a video discussing the
discovery. "We've determined what type of molecules regulate
self-renewal, which is the core property of these colon cancer stem
cells. It means we could address the big problem -- most people get
surgery and chemotherapy, but in half of people it comes back. And
we think the reason it comes back is because the cancer stem cells
actually survive therapy and can regrow the tumour."

According to statistics gathered by Cancer
Research UK, about 80 percent of sufferers undergo surgery that's
intended to cure the cancer, but it returns in half these
patients.

Over a four-year research period, Dick and his
team identified the gene BMI-1 as helping certain cells in the
colorectal cancer (otherwise known as bowel cancer) tumour
multiply. The gene was investigated specifically because of its
role in cell renewal in other cancers, including ovarian, prostate
and breast. Human bowel cancer was replicated in mice and the
team's suspicions about BMI-1's vital role in cell renewal were
confirmed.

Various BMI-1 inhibitors already exist, and Dick said
he and his team have been working with colleagues in the field and
companies to determine the best drug for blocking BMI-1. However in
their early experiments using a virus as an inhibitor, the gene was
successfully blocked in the mice, with stem cell content reduced "by between 100 to 1,000 fold".

"When we blocked the BMI-1 pathway, the stem
cells were unable to self-renew, which resulted in long-term and
irreversible impairment of tumour growth," said Dick. "In other
words, the cancer was permanently shut down.This is the
first step toward clinically applying the principles of cancer stem
cell biology to control cancer growth and advance the development
of durable cures."

According to Catherine O'Brien, senior coauthor
on the study, BMI-1 is a biomarker in 65 percent of all bowel
cancer cases, so the possibilities for using this technique are
great.

"With the target identified, and a proven way to
tackle it, this knowledge could readily translate into
first-in-human trials to provide more personalised cancer
medicine."

Potential side-effects must be rigorously
investigated first, however. As with an cancer treatment the
jeopardy of effecting other, healthy cells or functions remains a
significant risk. Chemotherapy might attack all cells, healthy and
otherwise, while surgery involves ensuring healthy margins are
dissected to account for any infection invisible to the naked eye.
With gene targeting, however, it's the other functions in the body
that need to be monitored when a particular molecule is
targeted.

When Wired.co.uk approached Dick to find out how far this
matter had already been explored, he responded: "Indeed, you point
out a potential concern for this kind of a target. We were very
careful in examining our xenografted mice and did not see any
obvious toxicity, especially to the colon which is also very
sensitive to BmI-1 loss. All of the murine models
reporting on BMI function used genetic ablation [blocking the gene]
while both our genetic silencing and drug treatment would have not
represented complete loss of function so that could be an answer as
to why we never saw toxicity."

It is possible that the treatment take place for only a brief
time, so as to avoid any undue complications caused by blocking
BMI-1.

"The colon cancer stem cells (CSC) are very sensitive to loss
of BMI-1 and only short term treatment is sufficient to induce loss
of CSC function," Dick tells Wired.co.uk. "Thus it is possible that
the colon CSC are much more sensitive to reduced BMI levels than
normal stem cells."

"However these are important issues for moving such drugs
onwards into more relevant toxicity assays before human trials can
initiate."